摘要
目的:
本研究旨在观察缺血后适应(IPost)对压力负荷诱导的肥厚心肌缺血再灌注(I/R)损伤的影响,并进一步探讨再灌注损伤抢救激酶(RISK)在IPost减轻肥厚心肌缺血再灌注损伤中的作用机制。本研究包括:1)通过显微外科技术建立小鼠主动脉弓缩窄压力超负荷模型,探讨心脏形态及功能变化的规律,确定心肌肥厚发生的时间点;2)建立小鼠离体肥厚心脏Langendorff缺血再灌注模型,研究缺血后适应对离体小鼠肥厚心肌缺血再灌注损伤中的保护作用,探讨再灌注损伤抢救激酶在该保护作用中的分子机制;3)探讨再灌注损伤抢救激酶中细胞外信号调节激酶(ERK1/2)作为Bcl-2与Bax的上游靶酶在IPost减少心肌缺血再灌注细胞凋亡中的作用。
方法:
课题第一部分:12周龄C57/BL小鼠通过主动脉弓缩窄(TAC)建立心肌肥厚模型,在1、4、8、12、16周时进行高频心脏超声、血流动力学、组织重量及心肌病理学检测,逆转录聚合酶链反应(RT-PCR)半定量测定心房利钠肽(ANP)、脑钠素(BNP)、α-肌球蛋白重链(α-MHC)、β-肌球蛋白重链(β-MHC)、转化生长因子(TGF-β1)、心肌内质网Ca2+-ATP酶(SERCA2a)mRNA的表达。
课题第二部分:12周龄C57/BL小鼠通过主动脉弓缩窄4周建立心肌肥厚模型,利用Langendorff灌流装置建立小鼠肥厚心肌I/R模型,稳定灌流30min,分为4组,1)I/R组:I/R组为停止灌流30min后直接恢复再灌注120min,在停止灌流前后不做任何特殊处理;2)IPost组(采取缺血10s及再灌注10s的3次IPost周期):停止灌流30min,在完全再灌注早期给予反复短暂灌流/停止灌流的后适应,之后持续120min的灌注;3)I/R+抑制剂组[分别用ERK1/2特异性抑制剂PD98059及蛋白激酶-B(Akt)特异性抑制剂wortmannin]:在恢复再灌注的开始不进行后适应循环,给予含抑制剂KH液持续灌流15min后,再恢复无PD98059的KH液灌流;4)IPost+抑制剂组:在再灌注120min起始,给予3次后适应循环的同时给予抑制剂的KH液持续灌流15min后,再恢复无抑制剂的KH液灌流。在再灌注120min时测定梗死心肌面积,采用微型测压球囊同步记录心功能的变化,分别在再灌注15min及2h时用Western印迹法测定左室心肌ERK1/2、核蛋白s6激酶(P70S6K)、蛋白激酶B(Akt)、糖原合成酶-3β(GSK-3β)蛋白表达。
课题第三部分:12周龄C57/BL小鼠通过主动脉弓缩窄4周建立心肌肥厚模型,利用Langendorff灌流装置建立小鼠肥厚心肌I/R模型,30min全心缺血随后再灌注120min。分为4组,I/R组、IPost组(采取缺血10s及再灌注10s的3次IPost周期)、I/R+PD98059组、IPost+PD98059组,进行心脏血流动力学、心肌梗死范围检测,Western印迹方法检测ERK1/2、Bcl-2、Bax、细胞色素C(Cyt.C)蛋白表达水平,脱氧核苷酸转移酶介导的生物素原位缺口末端标记(TUNEL)法检测心肌细胞的凋亡。
结果:
课题第一部分1)与假手术组比较,缩窄组左室收缩期及舒张期前壁和后壁厚度、左心室收缩末期及舒张末期内径于术后呈逐渐增加趋势;左心室射血分数于术后12周显著降低(P<0.05)。左室收缩压及左室压力上升和下降最大速率于术后4周明显增加,8～12周保持稳定,16周明显下降;左室舒张末压于术后8周持续增加(P均<0.05)。显示心肌由左室肥厚最终发展为心力衰竭。2)组织形态学天狼猩红测量心肌胶原含量及凋亡指数显示从4周到16周呈增加趋势;3)与假手术组比较,缩窄组心肌组织ANP、BNP、β-MHC、TGF-β1 mRNA术后1周至16周表达呈持续性增加;而α-MHC、SERCA2a mRNA表达呈持续性降低。
课题第二、三部分1)成功建立并改良了小鼠离体肥厚心脏Langendorff缺血后适应模型;2)与I/R组比较,IPost组的心肌梗死面积[(23.6±2.8)%]较I/R组[(40.2±4.6)%]明显降低(P<0.05);小鼠心脏血流动力学指标左心室收缩压、左心室压力变化最大速率显著改善(P<0.05);电镜观察发现IPost可减轻缺血再灌注引起的线粒体损伤;凋亡指数显著降低[(16±2)/100 vs(37±5)/100,P<0.05];3)与I/R组相比,IPost组心肌的再灌注15min及2h ERK1/2、P70S6K磷酸化蛋白水平显著增高,而Akt、GSK-3β磷酸化蛋白水平无明显变化(P均>0.05)。4)IPost组心肌的Bcl-2、线粒体Cyt.C表达显著增加,Bax、胞浆Cyt.C蛋白表达显著降低(P<0.05)。与I/R组比较,I/R+PD98059组、IPost+PD98059组上述指标无统计学意义(P均>0.05)。显示在再灌注的最初15min使用PD98059能消除IPost对肥厚心肌的上述保护作用并显著增加心肌梗死面积,与I/R组水平相同。
结论:
1)通过主动脉弓缩窄,可以建立稳定的小鼠压力超负荷诱导左室心肌早期代偿性向心性肥厚致晚期心力衰竭的动物模型;2)利用小鼠离体肥厚心脏Langendorff缺血再灌注模型,IPost能有效地减轻离体小鼠肥厚心肌缺血再灌注损伤,能明显减少心肌I/R损伤导致的线粒体损伤,减少心肌梗死面积,其中再灌注损伤抢救激酶中ERK1/2信号通路在再灌注早期即参与了IPost对缺血再灌注肥厚心肌保护作用,磷脂酰肌醇3激酶-蛋白激酶B(PI3K-Akt)信号通路未参与上述保护作用;3)ERK1/2信号通路对缺血后适应肥厚心肌的保护作用可能通过调控心肌细胞凋亡相关蛋白Bcl-2、Bax、Cyt.C的表达实现,其分子机制与上调胞膜Bcl-2与Bax蛋白表达的比值以及减少线粒体Cyt.C的释放有关。
Objective:
The research is aimed to evaluate effects caused by ischemia postconditioning (IPost) on mouse hypertrophic heart in vivosuffering from ischemia/reperfusion (I/R) injury, and further exploring cardioprotective mechanisms induced by reperfusion injurysalvage kinase (RISK)signal pathways in isolated mouse hypertrophic hearts. The presentstudy focuses on the following issues: 1) Through microsurgery to establish the transverse aortic constriction (TAC) mouse model and to explore the changed tendency of heartstructure and function. 2) To establish the advanced Langendorff model of mouse hypertrophic heart and to determine the effect of ischemic IPost protection in hypertrophic myocardiumsubjected to I/R injure and tostudy the role of RISKsignal pathways in mediatingsuch protection. 3) To explore the cardioprotective molecular mechanisms of extracellularsignal-regulated kinase 1/2 (ERK1/2) as the upstream target enzyme of Bcl-2 and Bax that decrease cell apoptosis.
Methods:
Part one:C57/BL wild mice, aged 12wk old, weresubjected tosham-operation (SH) or transversing aortic constriction to establish left ventricular hypertrophy. Echocardiographic assessments, hemodynamic determination, organ weight measurement, morphological and histological examination were performed at 1, 4, 8, 12 and 16 wks aftersurgery. At the meanwhile mRNA levels of atrial natriuretic peptide (ANP), Brain natriuretic peptide (BNP),α-myosin heavy chain (α-MHC),β-myosin heavy chain (β-MHC), Transforming growth factor (TGF-β1),sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) mRNA were determined by reverse transcription polymerase chain reaction (RT-PCR) technique. Part two: TAC was induced in aged 12 wks old C57/BL mice to establish left ventricular hypertrophy for 4 wks. Hypertrophic myocardium I/R injure was induced by 30min globe ischemia, followed by 15min or 120min reperfusion in Langendorff model. Hearts were randomly divided into 4 groups. 1) I/R group:30min global ischemia and 120min reperfusion; 2) IPost group:IPost with 3 episodes of 10s of ischemia and 10s reperfusion after 30min global ischemia and 15min or 2h reperfusion; 3) I/R+ inhibitor (ERK1/2 inhibitor PD98059 or Akt inhibitor wortmannin) group:after 30min global ischemia and then give 15min reperfusion by KH fuild with inhibitor PD98059 or wortmannin, then as I/R group; 4) IPost+inhibitor group:IPost with 3 episodes of 10s of ischemia and 10s reperfusion after 30min global ischemia and then with I/R+ inhibitor group. at the end of reperfusion the effects of IPost on infarctsize, hemodynamics bymini-balloon were measured;Protein levels of ERK1/2?P70S6K?Akt?GSK-3βwere determined by Western blot at the 15min or end of reperfuaion. Part three: TAC was induced in aged 12 wks old C57/BL mice to establish left ventricular hypertrophy for 4 wks. Hypertrophic myocardium I/R injure was induced by 30min globe ischemia, followed by 120min reperfusion in Langendorff model. Hearts were randomly divided into 4 groups:I/R group;IPos group (three cycles of 10s reperfusion interspersed by 10s of no–flow ischemia) ;I/R+PD98059 group; IPost+PD98059 group. At the end Hemodynamic determination, infarctionsize (IS) measurement were performed. Protein levels of ERK1/2, Bcl-2, Bax, mitochondrial and cytosolic Cyt.C were determined by Weatern blot. Apoptosis was measured by terminal deoxynucleotidyl transferase- mediated dUTP nick end labeling (TUNEL)staining.
Results:
Part one: (1) Compared withsH group, LVESd? LVEDd?Awsth?Awdth?Pwsth ? Pwdth ? progressive increased after TAC. Meanwhile, left ventricular fractionalshortening (LVFS%)significantly decreased at 16wk (P<0.05). LVSP ?dp/dtmax?dp/dtmin in TAC group were progressive increased after 4 wk. From 8~12 wk these parameters maintainedstabilization and thensharply decreased at 16 wk (all P<0.05). However LVEDP was increased at 8 wk and there wasstatistically difference (P<0.05). These echocardiographic and hemodynamic changes indicated a development of LVH and eventually progressing towards to heart failure. (2) Histologically, cardiac collagen measured by percentage ofsirius Red positivestained area and apoptosis indexshowed a progressive increase from 4 to 16 wk. (3) Compared withsH group, mRNA levels of ANP?BNP?β-MHC?TGF-β1was time-dependently increased whileα-MHC andsERCA2a were time-dependently decreased. (all P<0.05).
Part two and three: 1)The Langendorff model of mouse hypertrophic heart wassuccessfully established,;2)Infarctsize wassignificantly reduced in postconditioning group (23.6±2.8)% compared with I/R group hearts [(40.2±4.6)%, P<0.05], IPost group had higher Lvsp, dp/dtmax(all P<0.05); Myocardial function was equally improved compared with I/R group (all P<0.05); and apoptosis index decreased(AI%) [(16±2) /100 vs (37±5) /100, P<0.05] .3)ERK1/2?P70S6Kphosphorylation of myocardial wassignificantly increased in IPost group at 15min and 2 h reperfusion (all P<0.05).Compared with I/R, PI3K-Akt?GSK-3βphosphorylation of myocardial was nosignificantly changes in IPost group at 15min and 2h reperfusion (all P>0.05). 4)Compared with I/R group, increased protein levels of phosphorylated ERK1/2, Bcl-2, mitochondrial Cyt.C;decreased protein levels of Bax, cytosolic Cyt.C. I/R+PD98059 group had no effects on above-mentioned parameters. However, in IPost+PD98059 group, addition of ERK1/2 inhibitor PD98059, at the first 15min of reperfusion, reversed all changes observed in IPost group and eliminated IPost protection by increasing IS to a levelsimilar as in I/R group. The histopathological changes in mitochondria and myocardium destroyed by ischemia repefusion were alleviated markedly by ischemic postconditioning.
Conclusions:
The conclusion of the research can be drawn from the following four aspects, 1) Pressure-overload induced by TAC resulted in a development of LVH from early concentric hypertrophy to late eccentric hypertrophy. And eventually toward cardiac dysfunction or heart failure. 2) IPost plays a pivotal role in reducing ischemia/reperfusion injury by decrease AI and mitochondria injury in hypertrophic myocardium in vitro.ERK1/2signaling pathway involved in the protection of IPost, but PI3K-Aktsignaling pathway did not participate it. 3) ERK1/2signaling pathway involved in the protection of IPost by regulating the myocyte apoptosis proteins of Bcl-2?Bax and Cyt.C.IPost attenuated ischemia/reperfusion induced apoptosis via increasing the ratio of Bcl-2/Bax in mitochondrial, inhibiting mitochondrial Cyt.C release.
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